Fatty liver disease (FLD), whether it is alcoholic FLD (AFLD) or nonalcoholic FLD (NAFLD), encompasses a morphological spectrum of hepatic steatosis (fatty liver) and steatohepatitis. Alcohol is a well-known cause of fatty liver disease in adults, and can manifest histologically as steatosis, steatohepatitis, and cirrhosis. In recent years it has become evident that another entity, nonalcoholic fatty liver disease (NAFLD), can mimic the entire spectrum of hepatic changes typically associated with alcohol abuse. NAFLD is associated with insulin resistance, obesity, diabetes mellitus, hypertension, and dyslipidemias, collectively called the metabolic syndrome. The morphologic changes of alcoholic and nonalcoholic fatty liver disease are indistinguishable (Kumar, Abbas, Aster, Robbins Basic Pathology, 9th Ed.; Elsevier; 2013).
NAFLD is a condition defined by excessive fat accumulation in the form of triglycerides (steatosis) in the liver (>5% of hepatocytes histologically). A subgroup of NAFLD patients have liver cell injury and inflammation in addition to excessive fat (steatohepatitis). The latter condition, designated nonalcoholic steatohepatitis (NASH), is virtually indistinguishable histologically from alcoholic steatohepatitis (ASH). While the simple steatosis seen in NAFLD does not correlate with increased short-term morbidity or mortality, progression of this condition to that of NASH dramatically increases the risks of cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Cirrhosis due to NASH is an increasingly frequent reason for liver transplantation (Global Guidelines—Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis, World Gastroenterology Organisation, June 2012).
NASH is widely considered to be the liver expression of the metabolic syndrome. There is at present a worldwide epidemic of diabetes and obesity. At least 1.46 billion adults were overweight or obese and 170 million of the world's children were overweight or obese in 2008. The numbers are continuing to rise, indicating that NASH will become an increasingly common liver problem in both rich and poor countries, increasing the global burden of liver disease, and affecting public health and health-care costs globally.
Over the past couple of decades, it has become increasingly clear that NAFLD and NASH are now the number one cause of liver disease in Western countries. The prevalence of NAFLD has doubled during last 20 years, whereas the prevalence of other chronic liver diseases has remained stable or even decreased. More recent data confirm that NAFLD and NASH play an equally important role in the Middle East, Far East, Africa, the Caribbean, and Latin America.
PDE4 inhibitors have been evaluated in NAFLD with mixed results. Pentoxifylline appears to improve Liver Function Tests abnormalities by decreasing levels of alanine aminotransferase and/or aspartate aminotransferase (ALT and AST respectively) in both animal models and human studies without effecting cytokines such as TNF-α (Chae M K et al. Exp Diabetes Res 2012; 762565). However, in a Phase 1 clinical trial of ASP9831 by Astellas, after 12 weeks of treatment neither a 50 mg nor 100 mg daily dose demonstrated any significant difference in percentage change from baseline for either AST or ALT (Ratziu V, et al. Clin Gastroenterol Hepatol. 2014 Feb. 12. pii: S1542-3565). Thus, there remains a clear and unmet need to develop therapeutics for more effective treatment of liver disease and liver function abnormalities.
Other liver diseases having liver function abnormalities include inherited liver disorders (e.g. porphyria, Wilson's disease, and hemachromatosis); acute hepatitis (viral or bacterial infection, toxin exposure, and drug-induced hepatitis); autoimmune liver disease (e.g. primary biliary cirrhosis and lupus hepatitis); and biliary tract disease (e.g. sclerosing cholangitis). These diseases and pruritus associated with liver disease may benefit from treatment with a selective PDE4 inhibitor.